Evaluating improved inactivated oral cholera vaccines for use in ending endemic cholera by 2030: opportunities and challenges.

Cholera causes substantial morbidity and mortality in the world's poorest populations. For nearly a decade, an inactivated oral cholera vaccine (OCV) stockpile has been available to control and prevent outbreaks. In 2017, WHO launched a bold global initiative to reduce mortality from cholera by 90% by 2030, a cornerstone of which is deployment of OCVs from the global stockpile. The current production of OCVs for the stockpile falls well short of the doses needed to accomplish this goal. Besides efforts to enlist additional manufacturers of the current OCVs in the stockpile, inclusion of new-generation inactivated OCVs already in clinical development might offer advantages of enlarged production, improved performance, simplified logistics, and reduced costs. However, logistical, scientific, and ethical barriers make conventional, randomised, phase 3 clinical efficacy trials towards licensure of such new-generation OCVs problematic. The serum vibriocidal antibody response, the traditional immunological surrogate of protection against cholera, is imperfect for use as a standalone outcome. In this Personal View, we describe the need for new thinking on approaches for licensure and recommendations for new-generation inactivated OCVs, and suggest a pathway based on a sequential combination of immunogenicity and effectiveness observational studies.